Basal Cell Carcinoma
The basal layer of mammalian epidermis, or stratum germinativum, is the deepest layer of the five layers of the epidermis and produces new skin cells as existing cells die off. It forms a continuous layer of cells and becomes neoplastic, in most cases, after long-term exposure to ultra-violet light from the sun or artificial sources such as tanning beds that result in damage to the cells' DNA. Basal cell carcinoma (BCC) most commonly appears on skin of the head, neck, and arms and less often on areas of the body covered by clothing such as the trunk and legs. The appearance of BCC varies considerably, presenting as a growth or sore that does not heal or as a translucent, pink, pearly white, brown, black, or blue slightly raised growth. Occasionally, it may be a white, scar-like lesion called morpheaform BCC, with a waxy appearance. In rare cases, BCC can migrate to nearby muscle, nerve, or bone, causing loss or damage to these tissues. A schematic depiction of a BCC is shown in FIG. 1.
Current treatments for BCC include in-office surgical excision, cryosurgery (liquid nitrogen freezing), curettage-electrodessication, electro-surgery (burning with an electric needle), topical chemotherapy, with agents such as 5-fluorouracil (5-FU) and imiquimod, radiation (disks), electronic skin surface brachytherapy (ESSB), and laser therapy. Mohs surgery is used on larger BCC tumors with a high risk of recurrence and involves repeated surgical removal and freezing of cells, layer by layer, following immediate microscopic examination of each layer to determine if there are any remaining cancerous cells, until none are detected. This is followed by closure of the opening with sutures, skin grafts, or plastic surgery, if necessary. Mohs surgery has the highest rate of cure and is used often for BCC on the face where the need to preserve skin is paramount.
Glioblastoma
Glioblastomas are aggressive tumors that occur in the brain or spinal cord and form from a type of cell called an astrocyte; they are thus sometimes referred to as astrocytomas. According to Wikipedia, “Glioblastomas can contain more than one cell type (i.e., astrocytes, oligodendrocytes). Also, while one cell type may die off in response to a particular treatment, the other cell types may continue to multiply. Glioblastomas are the most invasive type of glial tumors as they grow rapidly and spread to nearby tissue. Approximately 50% of astrocytomas are glioblastomas and are very difficult to treat. Glioblastoma multiforme accounts for over 60% of all brain tumors in adults (Hanif et al., 2017, Asian Pac. J. Cancer Prev. 18:3-9). The incidence of glioblastoma is 3.19 per 100,000 (Thakkar et al., 2014, Cancer Epidemiol. Biomarkers Prev. 10:1985-96).
By the time one feels the symptoms of a glioblastoma, its tentacles are widespread in the brain. Injection into the tumor is currently not advisable because the tentacles wrap around the neurons of the brain without a visible center where the nucleus would normally be found in other cancers. Because there is no known method of locating the nucleus, injection into the tumor is usually ineffective.
To treat glioblastoma multiforme tumors with chemotherapeutics, the drug must cross the blood brain barrier (BBB). However, some treatments avoid passage through the BBB, e.g., radiation and immune modulator treatments. Fluorescent-guided resection is also employed for extracting out as much of the tumor tissue as possible (Stummer et al., 2000, J. Neurosurg. 93:1000-1013). MRI-guided laser ablation is another means of resecting as much malignancy as possible (Kubben et al., 2011, The Lancet 12:1062-1070), with the goal of extending survival. The U.S. Food and Drug Administration has also approved tumor-treating fields (TT Fields), a cap-like device which sends mild electrical charges through the skull to interfere with cancer cell division. The goal is to slow down a tumor's growth or metastic rate while avoiding harm to normal cells. TT Fields is not a cure but has the advantage of avoiding the pain, nausea, fatigue, or diarrhea associated with chemotherapy and radiation.
Irradiated boron isotopes (also known as boron-neutron recapture) have been explored as a way of targeting glioblastomas for several decades in recent clinical trials, patients with malignant glioblastoma treated with boron neutron recapture therapy in combination with standard radiation therapy survived significantly longer than those on standard therapy.
The main chemotherapeutic treatment for glioblastoma is temozolomide, an agent that alkylates/methylates DNA. Other agents include: carmustine, a dialkylating agent, lomustine, an alkylating agent; vincristine, which binds to tubulin proteins; cisplatin, an alkylating agent; bevacizumab, an angiogenesis inhibitor; etoposide, an inhibitor of DNA topoisomerase II; and procarbazine, an alkylating agent.
Coal Tar
Coal tar is made by heating coal in coke ovens to drive off volatile material. A description of the coking process can be found at the Cooper Creek Chemical Corporation website, under the reference titled “How is Crude Coal Tar Derived”. Coal tar is a mixed compound composed primarily of polycyclic aromatic hydrocarbons, including phenanthrene, acenaphthene, fluorene, anthracene, and pyridine. Coal tar is insoluble in water but mostly dissolves in benzene, and partially dissolves in alcohol, ether, chloroform, acetone, carbon disulfide, chloroform, and methanol.
Virtually all commercially available coal tar is produced as a byproduct of the manufacture of blast furnace coke from coal. Modern coke ovens are based on the dry distillation of coal in large horizontal chambers. The chambers are built of ceramic materials to allow heating the coal to temperatures exceeding 1,100 degrees centigrade. This dry distillation causes the coal to decompose into gas, liquid (tar), and solid coke. Gas and tar are collected in a series of condensers and coolers and processed to yield certain articles of commerce and a dry fuel gas.
The liquid product, coal tar, contains a complex mixture of hydrocarbons and other compounds containing variously, oxygen, sulfur and nitrogen. The key characteristic of all these coal tar components is their highly aromatic chemical structure, which is the result of the high temperatures in the coke oven.
When coal tar is used as a medicament, the pitch (27% of coal tar) may be boiled off above 400 degrees centigrade and may be removed from the final medicament by the supplier. Gas chromatography or HPLC can be used to assure that the coal tar USP used for treating basal cell carcinoma or glioblastoma contains no pitch and matches established consistency standards.
Recovery of specific coal tar fractions is initially based on their boiling range and is carried out in standard commercial distillation equipment. Emphasis is normally placed on the following three fractions in order of boiling range:
1. The light oil, BTX fraction. This fraction contains mainly compounds with a single aromatic ring, i.e., benzene, toluene and xylenes, hence the term “BTX.” The boiling points of these three compounds are, respectively, 80, 111, and 138-144 degrees centigrade.2. The naphthalene fraction. This contains most of the valuable chemical naphthalene, boiling point 218 degrees centigrade.3. Distillate fraction. This represents the remaining distillable fraction of the coal tar. The higher boiling non-distillable part, commonly referred to as pitch, is removed from the still as liquid. It usually represents more than half of the original tar.
The distillate fraction leaves the still as vapor from the top of the distillation tower and is condensed for recovery. The compounds which make up the main part of the distillate fraction are known as coal tar for medicinal purposes.
For further information concerning the above process, see the Kirk-Othmer Encyclopedia of Chemical Technology. 1997. New York: John Wiley & Sons, Inc. Volume 23. “Tars and Pitches.”
As a quality control measure, various methods known in the art may be used to monitor and quantify the top 17 fractions from the distillate fraction (see Example 4). For example, using classic column chromatography to separate the 17 fractions, monitoring by thin layer chromatography (TLC) where the mobile phase or eluent is pure hexanes (for the first 15 fractions), ethyl acetate (for fraction 16), and methanol (for fraction 17).
Therapeutic Uses of Coal Tar
One coal tar solution for topical use is described at the Universal Preserva-A-Chem Inc. website, under the product “coal tar topical solution USP”, where the chemical formula, properties, and some synonyms are listed. Coal tar solutions are often referred to as liquor carbonis detergens (LCD).
According to Wikipedia: “Coal tar was discovered around 1665 and used for medical purposes as early as the 1800s. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Coal tar is available as a generic medication and over the counter. Coal-tar was one of the key starting materials for the early pharmaceutical industry.”
Coal tar is available in the United States in a US pharmacopeia (USP) grade with a maximum residue on ignition of 2.0%. Coal tar ointment USP (obtained by combining coal tar with polysorbate 80 (a sorbitan mono-oleate polyoxyethylene derivative) and blending with zinc oxide paste) and coal tar topical solution USP (made by combining coal tar with polysorbate 80 and diluting with ethanol to an ethanol content of 81.0-86.0%) are also available in the United States.
Coal tar USP is approved for use in the United States in denatured alcohol, formula 38-B and 38-F. Numerous products, coal tar strengths, dosage forms, routes of administration and brand or generic forms are available. Coal tar USP is known to penetrate to the stratum germinativum.
Raw coal tar is known to pass through the blood brain barrier (BBB) and have neurological effects. The BBB protects the brain from noxious, electrically charged chemicals that circulate in the blood by preventing them from entering the brain. Therefore, to pass through the BBB, a pharmacologic agent should be non-polar.
The American Society of Health-System Pharmacists; Drug Information 2016. Bethesda, Md. describes the well-established uses of coal tar products for dermatological conditions. Coal tar has been used in the management of dandruff, seborrheic dermatitis, and psoriasis, where it reduces the number and size of epidermal cells produced. This has led to the suggestion that coal tar extracts oxygen from the skin, thereby inhibiting cell reproduction (mitosis) and causing a decrease in the size and number of cells in the stratum germinativum and stratum corneum. Another suggestion is that coal tars formulated in various soaps and shampoos exert their therapeutic action in patients with dandruff, seborrheic dermatitis, or psoriasis by penetrating the epidermis and removing the scales produced by these skin disorders. Polyphenolic substances and peroxides in coal tar may react with epidermal sulfhydryl groups to produce an effect on skin that is similar to that resulting from exposure to sunlight. This effect could theoretically decrease epidermal proliferation and dermal infiltration.
Coal tar preparations are used topically alone or in combination with other drugs (e.g., salicylic acid or sulfur) for controlling dandruff, seborrheic dermatitis, or psoriasis. Although there are few well-controlled studies demonstrating their efficacy, coal tar preparations are used and generally considered effective for relieving the itching and scalp flaking associated with dandruff; for relieving the itching, irritation, and skin flaking associated with seborrheic dermatitis; and for relieving the itching, redness, and scaling associated with psoriasis.
A combination of coal tar components for the treatment of disorders responsive to dihydrofolate reductase (DHFR)-inhibition is disclosed in U.S. Pat. No. 6,337,337. DHFR catalyzes the NADPH-dependent reduction of 7,8-dihydrofolate (H2F) to 5,6,7,8-tetrahydrofolate (H4F) and is necessary for maintaining intracellular levels of H4F, an essential cofactor in the synthetic pathway of purines, thymidylate, and several amino acids. The inventive coal tar compositions described in the '337 patent are believed to inhibit the transfer of the hydrogen ion on NADPH to dihydrofolate reductase, thus preventing metabolism within the nucleus of tetrahydrofolate. Because neoplastic cells are more responsive than slower-dividing normal cells to this resulting interference with DNA synthesis, repair, and cellular replication, cancers responsive to antifolate therapy as delineated in the '337 patent do not divide and are known to “explode” upon treatment with coal tar products. The '337 patent describes compositions of coal tar as functionally replicating the antifolate methotrexate for the treatment of certain cancers.
Toxicity of Coal Tar
A comprehensive review of the toxicity of coal tar by the U.S Department of Health and Human Services appeared in 2002 and can be found in the creosote toxicology profile found at the Agency for Toxic Substances and Disease Registry's website. The document reviews studies that provided mixed evidence as to whether coal tar causes squamous cell carcinoma and other tumors. Much of the research reviewed concerned long-term occupational exposure in the air or in the factory, often decades in the past, when industrial standards of hygiene and worker safety were not as strict as at present. Furthermore, where evidence of tumorigenicity was purportedly found, the effects observed may have required a combination of chronic exposure to coal tar or its products and exposure to sunlight.
Notably, studies did not find a statistical correlation between the use of coal tar products on human skin and cancer incidence. Perhaps the best data on human coal tar use came from users of coal tar for psoriasis. In particular, a study by Bhate et al., summarized on page 136 of the government review, used a large population, was placebo controlled, and the cancers sought were extensive. The study found that the incidence of cancer (total, skin, breast, cervix, genitourinary tract, bronchus, gastrointestinal tract, lymphoma, or other) was not significantly greater in 2,247 patients with psoriasis than in 4,494 age-matched controls without psoriasis.
In other studies, reproductive risks in humans were not found, and despite many reported studies in the review, none could identify a biological risk of any significance to humans (other than benign tar warts among creosote tar workers with 5 to 40 year exposures), including to the central nervous system.
There were also studies that examined the effects of some of the constituents of coal tar (as opposed to the effects of coal tar as a whole). Although some of the studies reviewed would be considered inadequate by current standards, the results nevertheless indicate that coal tar creosote and its constituents can induce skin tumors as well as act as tumor initiators and promoters. Nevertheless, the International Agency for Research on Cancer, the American Conference of Governmental industrial Hygienists, the National Toxicology Program, and the Occupational Safety and Health Administration reported that no component of coal tar present at levels greater than or equal to 0.1% is identified as a probable or confirmed human carcinogen.